Neurogenic inflammation and neuropathic pain are mediated by the mechanical damage of peptidergic sensory nerves (in case of traumatic neuropathy) or chemical activation of peptidergic sensory nerves (in case of neurogenic inflammation), resulting in pathological activation and dysfunctions of peptidergic sensory nerves. The undesired activation and dysfunction is implicated in severe hyperalgesia (the threshold of a painful stimulus causing nocifensive behaviour remarkably decreases) and allodynia (non-painful stimulus becomes painful and induces nocifensive behaviour).
Traumatic neuropathy induced by mechanical nerve damage (e.g. suffered in accidents, bone fractures or operations) is mediated by complex mechanisms at the levels of both the peripheral and central nerve endings in the respective innervated region, spinal dorsal horn and other pain-related brain regions. Neuropathies caused by traumatic events (mechanical damage-induced axonopathies) affect only one or a few anatomical structures (mononeuropathy) and result in pathological activation and dysfunctions of peptidergic sensory nerves. In these cases, neuropathic pain is caused by different mechanisms compared to metabolic or toxic polyneuropathies, such as abnormal crosstalk between sensory and sympathetic nerves, changes in the expression of different ion channels, marked glial cell activation etc., and mediated by different signaling molecules than in diabetic neuropathy (Banoliel R et al., Oral Dis., 2012, 18(4):317-32; Aley K O. and Levine J D, Neuroscience., 2002, 111(2):389-97). There are also differences in the therapy of diabetic and traumatic neuropathies. Causal pharmacotherapeutic agents (alpha-lipoic acid, benfotiamine) exerting an action based on the pathophysiological mechanism of the disease is only available in diabetic, but not in traumatic neuropathy (Miranda-Massari J R et al., Curr Clin Pharmacol., 2011, 6(4):260-73). Drugs used as symptomatic therapy for diabetic neuropathic pain include antidepressants, anticonvulsants, opioids and some other groups (e.g.: topical lidocain, capsaicin). Their effectiveness is well documented by clinical evidence-based data in painful polyneuropathies (such as diabetic) and postherpetic neuralgia, but not in traumatic neuropathy. Additionally, these drugs do not treat the cause of neuropathic pain and are not effective in a large proportion of patients (Finnerup et al., Pain., 2010, 150(3):573-81).
Peripheral and central sensitization mechanisms play important roles in the development of severe persistent chronic pain induced by mechanical nerve damage, which is not effectively treated by the conventional analgesics. Therefore, intensive traumatic neuropathic pain is a clinically challenging problem, since opioids and cyclo-oxygenase (COX) inhibitor non-steroidal anti-inflammatory agents (NSAIDs) are not potent in these conditions. Adjuvant analgesics, such as certain antiepileptics and antidepressants acting in the central nervous system (CNS) by inhibiting the ascending pain pathway and/or activating the descending inhibitory pathway can be used in some patients, but they cannot be regarded as optimal therapeutic solutions for the problems due to severe acute side effects (cardiovasular, CNS) and/or chronic toxicity.
Furthermore, neurogenic inflammation (vasodilatation, plasma protein extravasation, inflammatory cell activation) induced by the stimulation of peptidergic sensory nerves and the released pro-inflammatory sensory neuropeptides (substance P, calcitonin gene-related peptide) play a very important role in a variety of different acute and chronic inflammatory painful diseases (Chiu et al., Nat. Neurosci., 2013, 15(8):1063-7), although it is not the exclusive mechanism. This is a basically different inflammatory mechanism compared to immune cell-mediated processes, it is often the very early initiation step even in chronic diseases, which triggers and then remarkably augments further cellular pathways. The neurogenic inflammatory component is not inhibited by the conventional anti-inflammatory drugs (COX inhibitors), and glucocorticoids are only moderately effective in extremely high doses in which they exert very many severe side-effects that limit their clinical applications. Therefore, it is particularly important to identify novel therapeutical mechanisms and targets to inhibit neurogenic inflammatory pain. This could substantially help the treatment of chronic inflammatory disorders providing long-term therapeutical benefits for a great patient population.
Subject molecules of the present invention are new and have been identified as active agents in neurogenic inflammation and neuropathic hyperalgesia models. Although compound (a) has very similar structure, it was published as antimicotic substance (Chimica Therapeutica vol 6. (1971) 427-437) and was found totally inactive in the analgesic and anti-inflammatory models, which are shown within the examples of the present invention. This finding supports our “theory of methoxy groups”. Dimethoxy is not allowed in general formula (I) of the present invention on R1 phenyl and monomethoxy is more tolerable on R4 phenyl compared with dimethoxy substitution in analgesic and anti-inflammatory activity point of view.
Related N-benzylidene-N′-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-hydrazine derivates in WO2005105804 patent have analgesic and anti-inflammatory effect. These anti-inflammatory agents of formula (b) contain hidrazone moiety, controversially to the substances of the present invention, which have methylene-amino group at the same position. Surprisingly this replacement of hidrazone moiety with methylene-amino one has not ruined the analgesic and anti-inflammatory activity of the invented substances.

Further dimethoxy-4-phenetylamino-7H-pyrrolo[2,3-d]pyrimidine derivatives (a1) to (a4) are disclosed under CAS Registry Number 951981-71-8, 929850-23-7, 906261-62-9 and 903852-84-6, respectively. Although there is no information relating to their effect, if any, these compounds overlap with the general formula (I) (see below), therefore they are excluded from the claimed scope.
WO 94/13676 A1 discloses a general formula which encompasses compounds having similar structure to that of the claimed ones but there is no methylene moiety between the N of the 7H-pyrrolo[2,3-d]pyrimidin and the aryl (R1 in the present general formula I). The claimed compounds are corticotropin releasing factor antagonists and they are used for treating CRF induced illnesses or inflammatory diseases such as arthritis, asthma and allergies. Closest possible compounds embraced by the scope are not disclosed by examples, moreover, in the examples the moiety corresponding to our R4 in most cases is other than aryl. When R4 is aryl, the moiety linking said aryl to the pyrrolo-pyrimidine comprises N or O. Furthermore; the document does not contain any biological data confirming the claimed pharmaceutical effect.
Structurally similar compounds are disclosed in WO 03/031447 but they are substituted in position 2 of the pyrrolo-pyrimidine ring. Said compounds show a phosphodiesterase V inhibitiory activity and can be used for treatment of diseases of the coronary circulatory system and for treatment and/or therapy of potency disorders.
Compounds having 7H-pyrrolo[2,3-d]pyrimidine backbone and substituents different from that of the present invention as defined below are described in U.S. Pat. No. 6,686,366. The invention relates to compound effective in the treatment of diseases associated with A3 adenosine receptors. Said diseases are respiratory disorder or gastrointestinal disorder, for example diarrhea, asthma, allergic rhinititis and the like. The document thoroughly describes the role of several different substituents which are linked to different position of the pyrrolo-pyrimidine skeleton in the inhibition of said A3 adenosine receptors.